On May 2025, a study published in the journal Current Biology by researchers from Stanford School of Medicine found that orange cats have a unique gene mutation. This mutation is located on the X chromosome, which increases the activity of the nearby Arhgap36 gene, causing the abnormal expression of Arhgap36 in pigment cells and inhibiting the intermediate link of the molecular pathway that controls coat color. This mutation is only found in the domestic cat species and is related to gender, being more common in male orange cats.
The mutation is a 5 – kb non – coding region deletion near the Arhgap36 gene on the X chromosome. This deletion may rearrange conserved regulatory elements to form a new enhancer – activation site, specifically activating the expression of Arhgap36 in pigment cells. The abnormal expression of Arhgap36 inhibits the protein kinase A (PKA) signaling pathway, disrupting the MC1R – cAMP – PKA melanogenesis axis, reducing eumelanin and increasing pheomelanin, thus producing the orange coat color.
In female cats, due to the random inactivation of the X chromosome (XCI), cats carrying this deletion show patchy orange – and – black coat colors (tortoiseshell or calico cats), which is a classic example of the Lyon hypothesis. Since male cats have only one X chromosome, any male cat carrying the mutation will be fully orange, while female cats need to inherit the mutated X chromosome from both parents to be fully orange, which is rarer. Therefore, most orange – haired female cats are mottled in color, such as calico or tortoiseshell, and may also include black and white.
The deletion mutation is shared by orange cats worldwide, suggesting a single origin. It is estimated to have originated about 900 years ago, long after the domestication of cats but before the breeding of cat breeds. This mutation may cause mild skin abnormalities (such as freckle – like lesions) in cats, but it does not show other obvious pathogenic effects.
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